Menopausal Symptoms & Management PHARMACY PROFESSIONAL REVIEW COURSE SPRING 2011-2012 Ph. Anand Davidson.

Definition: Menopause is defined as the permanent cessation of menstruation resulting from loss of ovarian follicular activity. The phase in the aging process of women marking the transition from the reproductive stage of life to the non-reproductive stage It is signalled by the last menstrual period The average age of menopause is 51.

Two Phases: 1. Perimenopausal Phase Women will experience erratic periods before the final cessation due to inadequate ovarian oestrogen secretion and this transitional phase lasts around 4-5 years 2. Postmenopausal Phase The occurrence of the last menstruation usually taken as being final if it is followed by a 12-month blood-free interval.

Menopause - Types Premature menopause – before 40 years Surgical menopause – hysterectomy, oophorectomy Natural menopause – mean age 51 years Late Menopause – after 55 years DIAGNOSIS: High FSH level ( >30iu/L) Low estradiol level ( <100pmol/L) The problems associated with the menopause result from oestrogen deprivation

Vasomotor symptoms: hot flushes, night sweats and palpitations Menopausal symptoms Vasomotor symptoms: hot flushes, night sweats and palpitations Urogenital atrophy: vaginal dryness, dyspareunia, pruritus vulvae, urinary frequency, urgency, and recurrent cystitis Psychological symptoms: irritability, nervousness, depression, insomnia , anxiety and decreased libido Osteoporosis: loss of calcium from the bones, frequent fractures Coronary heart disease: change in blood lipid profile

Management of menopause Advise on a healthy life style Psychological support Hormone replacement therapy Venlafaxine, Clonidine Tibolone, Raloxifene and the bisphosphonates

Management of menopausal symptoms Understand menopause Strengthening of self-image Avoid spicy food, alcohol, strong tea and coffee. Healthy life style Hormone Replacement Therapy

Prevention of osteoporosis Change lifestyle risk factors Exercise Adequate calcium / vitamin D intake Hormone Replacement Therapy Tibolone Alendronate Raloxifene

Possible mechanism of Cardioprotection by HRT Favourable lipid profile:  HDL,  LDL,  Lipoprotein (a) Other effects:  insulin sensitivity, vascular dilatation,  coagulation factors

Indications for HRT Relief of menopausal symptoms Long term prevention of osteoporosis

Absolute contraindications Undiagnosed postmenopausal vaginal bleeding Oestrogen dependent tumour Venous thrombo-embolism / stroke Acute liver disease

Routes of administration for oestrogens in HRT. Oral Transdermal (patches/gels/cream) Intranasal Subcutaneous (Implants) Vaginal (creams and medicated rings)

Oral therapy Natural occurring oestrogens: includes conjugated estrogen and various oestradiol preparations. These oestrogens are metabolised in the liver to the weaker metabolite oestrone and then converted to oestradiol in the peripheral circulation and in the target tissue. Tibolone: a steroid hormone that has oestrogenic, progestogenic and androgenic properties. Synthetic oestrogens: such as mestranol or ethinyl oestrodiol are not generally prescribed for older women for HRT.

Transdermal therapy Patches (oestrogen only or combined preparation) or oestrogen gels Women’s preference Skin irritation may be a problem but new matrix patches and the gels are usually well tolerated Route of choice for women with risk factors for venous thrombo-embolism, liver disease or gastro-intestinal problems

Treatment of Menopausal symptoms with Estrogen Gold standard for relief of menopausal symptoms Contraindications-breast cancer, CHD, venous thromboembolism/stroke Duration- 6 months to 5 years Dose- low-dose is recommended Conjugated estrogens 0.3mg or Estradiol 0.5mg Adding a Progestin-to prevent endometrial hyperplasia and cancer with unapposed estrogen therapy (medroxyprogesterone 1.5mg daily)

Treatment of Menopausal symptoms with Estrogen Low-dose oral contraceptives- low estrogen oral contraceptive-20mcg of ethinyl estradiol to treat perimenopausal symptoms

Treatment of vasomotor instability in women not taking estrogen Venlafaxine 75mg daily – reduces hot flushes by 61% Side effects- Dry mouth, anorexia, nausea, constipation Clonidine Hcl- 50mcg to 75mcg twice daily

Treatment of Urogenital changes Sexual function – systemic or vaginal estrogen therapy to treat decreased vaginal lubrication, decreased sexual function and Dyspareunia Urinary incontinence - systemic or vaginal estrogen Urinary tract infections – suitable antibiotics

Treatment of urogenital atrophy in women not taking systemic estrogen Vaginal moisturizers and lubricants – Astroglide Low-dose vaginal estrogen – concomitant progestin theapy is not necessary Vaginal ring estradiol-delivers 6 to 9 mcg / day for a period of 3 months Conjugated estrogens vaginal cream-0.5g of cream / 1/8th of the applicator full daily for 3 weeks followed by twice weekly

Treatment of urogenital atrophy in women not taking systemic estrogen Estradiol vaginal cream- cream-0.5g (50mcg of estradiol)of cream / 1/8th of the applicator full daily for 3 weeks followed by twice weekly Estradiol vaginal tablet- each vaginal tablet contains 25mcg of estradiol – twice/week

Nonpharmacologic therapy of Osteoporosis Diet- rich in calcium and vitamin D Calcium- daily 1000 to 1500mg of elemental calcium in divided doses with meals Vitamin D- 400 to 800 IU daily Exercise- at least 20 minutes of weight bearing exercises daily to reduce rate of bone loss Cessation of smoking to reduce bone loss

HRT regimens Women who have had a hysterectomy only need to take oestrogen Women with an intact uterus must take progestogen for endometrial protection to prevent endometrial cancer or hyperplasia Regular surveillance of endometrium is required for women (extreme intolerance of progestogen) on unopposed oestrogen

HRT regimens Sequential preparation: progestogen added for 12-14 days each month. Some women will not bleed on sequential preparations and this is not a cause for concern provided that the progestogen is taken correctly. Continuous combined HRT: give oestrogen and progestogen daily. These preparation induces endometrial atrophy. Intermittent bleeding and spotting are common in the first few month of use. More suitable for women who are at least one year since their last spontaneous period.

Progestogen Oral or transdermal form Levo-norgestrel releasing intra-uterine system

Oral progestogens C21 progesterone derivatives : dydrogesterone or medroxyprogesterone acetate C19 nor-testosterone derivatives: norethisterone acetate or levonorgestrel

Side effects of HRT Nausea breast pain heavy or painful withdrawal period premenstrual syndrome type of side effects weight gain

Risk of HRT Breast cancer Thrombo-embolism

HRT and venous thrombo-embolism Natural oestrogens Women taking HRT have a 2-4 fold increase in risk of venous thrombo-embolism (VTE). Overall risk remain small: 1 in 5000 and mortality from VTE is around 1-2%. Women with significant past history of VTE should have a thrombophilia screen before commencing HRT

Menopausal symptoms Duration of treatment will depend upon the women’s preference and the presence of risk factors In the absence of risk factors, HRT can be stopped after 2 years

Monitoring of women on HRT Compliance of treatment, symptoms control, side effects and bleeding pattern Cervical smear

Other options for management of menopausal symptoms and prevention of osteoporosis Tibolone: Steriod hormone The parent compound and its metabolites can all bind to steroid receptos Oestrogenic, progestogenic and androgenic properties Different hormonal effects predominate in different tissues. Oestrogenic: climacteric symptoms, bone and lipid Progestogenic: endometrium Androgenic: libido Breast: less breast pain and no change in breast density on mammography

Other options for prevention of osteoporosis Bisphosphates: Etidronate and Alendronate Inhibitors of bone turnover and slow down or prevent bone loss Both need to be taken on an empty stomach Non-hormonal agents Treatment of choice for older women and those with contra-indications to HRT

Prevention and treatment of Osteoporosis- Other Options Screening of Osteoporosis – Measurement of BMD Bisphosphonates- adsorbed on to hydroxyapatite crystals in bone, slowing both their rate of growth and dissolution, and therefore reducing the rate of bone turnover. Alendronate sodium Treatment-10mg / day or 70mg once a week Prevention- 5mg / day or 35mg / week Risedronate sodium Prevention and treatment- 5mg / day or 35 once per week

Bisphosphonates Alendronate or risedronate should be taken with a full glass of water 30 minutes before the first meal or beverage of the day. Patients should not lie down for atleast 30 minutes after taking the dose to avoid the unusual complication of pill-induced esophagitis Disodium etidronate 200mg daily for 14 days Avoid food, calcium containing products, iron and mineral supplements, antacids for atleast 2 hours before and after oral treatment.

Prevention and treatment of Osteoporosis- Other Options Raloxifene- a selective estrogen receptor modulator Prevention and treatment of osteoporosis – 60mg/day Strontium Ranelate- treatment of post menopausal osteoporosis to reduce risk of vertebral and hip fractures- 2g once daily in water, preferably at bed time Avoid food, calcium containing products, iron and mineral supplements, antacids for atleast 2 hours before and after oral treatment. Tibolone- Osteoporosis prophylaxis- 2.5mg daily

Selective oestrogen receptor modulators (SERMs) Raloxifene Selective oestrogen receptor modulators (SERMs) Agonist and antagonist properties Bone protective and reduce cholesterol No effect on the endometrium Evidence to suggest that it is protective against breast cancer Does not help menopausal symptoms and may worsen them